Dysfunctional cGMP Signaling Leads to Age-Related Retinal Vascular Alterations and Astrocyte Remodeling in Mice

• Published in: International journal of molecular sciences Vol. 23; no. 6; p. 3066
• Main Authors: Holden, Joseph M, Al Hussein Al Awamlh, Sara, Croteau, Louis-Philippe, Boal, Andrew M, Rex, Tonia S, Risner, Michael L, Calkins, David J, Wareham, Lauren K
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 12.03.2022; MDPI
• Subjects: Acuity; Age; Animals; astrocyte; Astrocytes - metabolism; Bioavailability; blood retinal barrier; Blood vessels; connexin; Cyclic GMP; Cyclic GMP - metabolism; Cytology; Degeneration; gap junctions; Genotype & phenotype; Glaucoma; Glial fibrillary acidic protein; Guanylate cyclase; Intraocular pressure; Mice; Mice, Knockout; Morphology; Neurodegeneration; neurovascular unit; Nitric oxide; Nitric Oxide - metabolism; Pathology; Retina; Retinal ganglion cells; retinal vasculature; Signal Transduction; Visual acuity; Visual observation; gap junctions; neurodegeneration; astrocyte; blood retinal barrier; retinal vasculature; connexin; retinal ganglion cell; neurovascular unit
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms23063066

The nitric oxide-guanylyl cyclase-1-cyclic guanylate monophosphate (NO-GC-1-cGMP) pathway is integral to the control of vascular tone and morphology. Mice lacking the alpha catalytic domain of guanylate cyclase ( ) develop retinal ganglion cell (RGC) degeneration with age, with only modest fluctuations in intraocular pressure (IOP). Increasing the bioavailability of cGMP in mice prevents neurodegeneration independently of IOP, suggesting alternative mechanisms of retinal neurodegeneration. In continuation to these studies, we explored the hypothesis that dysfunctional cGMP signaling leads to changes in the neurovascular unit that may contribute to RGC degeneration. We assessed retinal vasculature and astrocyte morphology in young and aged and wild type mice. mice exhibit increased peripheral retinal vessel dilation and shorter retinal vessel branching with increasing age compared to Wt mice. Astrocyte cell morphology is aberrant, and glial fibrillary acidic protein (GFAP) density is increased in young and aged mice, with areas of dense astrocyte matting around blood vessels. Our results suggest that proper cGMP signaling is essential to retinal vessel morphology with increasing age. Vascular changed are preceded by alterations in astrocyte morphology which may together contribute to retinal neurodegeneration and loss of visual acuity observed in mice.